The application is fore renewal of a long-standing Program Project. The focus of the currently funded grant and that of the renewal is on the role of the peripheral nervous system and the spinal cord in pain mechanisms. Animal modes of human pain states are used so that experimental manipulations can be employed to provide evidence for pathophysiological mechanisms of pain of potential improvements in therapy. The theme of the Program Project is the role of inflammation in a number of clinically in a number of clinically important pain states. These include visceral, arthritic, peripheral neuropathic and central neuropathic pain. Multi-disciplinary approaches are taken in each project. Project 1 investigates the role of a newly described visceral nociceptive pathway in the dorsal column in mediating genitourinary, as well as gastrointestinal pain. Sensitization of primary visceral afferents and ventral viscerosensitive postsynaptic dorsal column and spinothalamic tract cells will be studied in vivo and in vitro. Project 2 examines the contribution of glutamate to neurogenic inflammation in the knee joint. The effects of glutamate in releasing cytokines and chemokines will be studied in vivo and also in vitro, using cultures of synoviocytes. Project 3 considers dual roles of the sympathetic nervous system in neuropathic pain. Up-regulation of adrenoreceptors, purinoceptors and NPY receptors on axotomized afferents on non-axotomized primary afferents will be investigated. The role of inflammation will be examined. Project 4 is concerned with changes in neuropeptide expression in a model of spinal cord injury, hemisection of the cord. Peptides that change include galanin, substance P, and calcitonin gene-related peptide. These are regulated in opposite directions by leukemia inhibitory factor and nerve growth factor, and so the effects of manipulations of these substances on peptide expression and nociception will be examined. The projects will be supported by 4 cores. Core A is an Administrative Core and will provide coordination of the budgets and of interactions amongst the group, consultant help with statistics and experimental design, and computer services. Core B is an Electronics Core and will provide assistance with equipment failures and with the design and construction of electronic devices that are not commercially available. Core C is an Imaging core and will support the projects by providing assistance with confocal microscopy and image analysis. C is an Imaging core and will support the projects by providing assistance with confocal microscopy and image analysis. Core D is a Neurochemistry/Molecular Biology Core and will help the projects with standardized chemical and molecular biological assays.